Cyclin D1, at the center of MCL pathogenesis. Cyclin D1 mRNA stability and translation is increased by the PI3K/AKT/mTOR pathway. Cyclin D1 translocates into the nucleus and forms a holoenzyme with CDK4/6 to phosphorylate the retinoblastoma protein (RB), resulting in the release of E2F transcription factors and G₁/S phase transition. In addition, cyclin D1/CDK4 complexes have kinase-independent functions, notably binding of the cell-cycle inhibitor p27kip, which is thereby titrated away from cyclinE/CDK2 complexes further promoting cell-cycle progression. Cyclin D1/CDK4 inhibits degradation of CDT1, the rate-limiting factor in DNA replication. Stabilization of CDT1 in S phase can induce the replication of already transcribed chromosomal segments, giving rise to increased numbers of double strand breaks and activation of DNA damage checkpoints. In S phase cyclin D1 is phosphorylated on threonine 286 by GSK3β, exported from the nucleus by CRM-1, polyubiquitinated by the E3 ligase SCF(FBX4-αB Crystallin), and degraded through the proteasome (reviewed in Kim and Diehl ²⁸ ). GSK3β is phosphorylated and inactivated by AKT and WNT signaling. Several components of this cell-cycle control machinery are altered in MCL: blue symbols (Δ) indicate molecules inactivated or down-regulated; red symbols, molecules activated or overexpressed. Illustration by Paulette Dennis.